The goals of this proposal are to identify and to understand the mechanism of action of the iddm4 gene, a critical non-MHC determinant of susceptibility to autoimmune diabetes in the BB rat. We have shown that the BB-origin allele at iddm4 has 79% sensitivity and 80% specificity in predicting diabetes susceptibility. To identify iddm4, we have generated the necessary tools and reagents, including a congenic iddm4 rat with a 2.8 cM region on the diabetes-resistant WF strain that is susceptible to diabetes and a radiation hybrid map of the iddm4 interval with a catalog of the candidate genes in this region. Specific Aim 1 is to generate congenic lines of rats with progressively smaller iddm4 intervals and to fine map the iddm4 region. Specific Aim 2 is to identify molecular and biological phenotypes associated with iddm4. We have shown that bone marrow, thymocytes, and peripheral T cells from BB rats, and thymocytes from WF congenic rats bearing the BB-origin iddm4 interval are capable of the adoptive transfer of diabetes. We hypothesize that iddm4 mediates its diabetogenic effects by expression in hematopoietic-origin cells during intrathymic development. Specific Aim 3 is to identify iddm4. We will identify iddm4 by a combination of bioinformatics, susceptibility testing, and functional assays. To achieve this goal, we will continue our close collaborative arrangement between cellular biologists at the University of Massachusetts Medical School and molecular geneticists at the Drexel University College of Medicine. Although centered on studies of diabetic rats, the real significance of this proposal is its relevance to human diabetes. With the sequence of the human genome now available, NIH and the Juvenile Diabetes Research Foundation (JDRF) have established a human type 1 diabetes genetics consortium to identify those genes that confer susceptibility to the disease. An important component of this strategy is to identify resistance and susceptibility loci in mouse and rat models of type 1 diabetes. The NIH/JDRF goal is to use available mouse and rat genome sequence and orthologue maps to translate discoveries in animal models to humans. The genetic effect of iddm4 is large, and this work has will identify a major non-MHC susceptibility locus for autoimmune diabetes mellitus. The work we propose in the BB rat has the potential to contribute to that national goal.